IV. TR&D2 - Abstract The overall goal of this project is to develop the next generation computer simulation platform for spatially realistic simulation and analysis of cellular and subcellular biochemistry. Cellular systems, especially in neurons, are profoundly difficult to understand because of the interplay between spatial, biochemical and molecular complexity that occurs on multiple levels of organization, from macromolecular assemblies to synapse architecture to neural circuits. Biological complexity is daunting and scientific investigators must persevere to finds ways to overcome it. This is important because Scientific Discovery is driven by testable hypotheses which derive from our intuition and questions surrounding our current understanding of reality. But when daunting complexity confounds our intuition we struggle to conceive new hypotheses and the cycle of discovery grinds to a halt. Computational models allow investigators to probe the complex relationships between biological components, obtain new insights and intuition -- the genesis of new hypotheses. The MCell/CellBlender platform for cell modeling we are developing is expressly designed to fulfill this need, providing insight and understanding of complex cellular systems. The cell modeling tools we develop here are designed to mesh with the molecular, network, and image-derived modeling tools of TR&Ds 1, 3 and 4. The tools will be used by our Driving Biomedical Project research partners to study neuronal and synaptic structure and function and the intricate biochemical pathways involved in learning and memory in the brain. The detailed level of understanding of these systems afforded by computational modeling of these systems will provide new insights that may be applicable to many types of cell signaling pathways, and in particular should help to elucidate how dysfunctions in cell signaling may contribute to neurological and psychiatric pathology.